The p53 tumor suppressor gene is mutated in the majority of human cancers. Alterations in p53 are an early event in the pathogenesis of multistage lung and esophageal carcinomas. The mutational spectrum of p53 in different human cancer types and, in some cases, the mutations are a DNA fingerprint of environmental carcinogen exposure. Initial results indicate differences in p53 mutational spectra in lung cancers from uranium miners versus non-miner cigarette smokers. Mechanistic studies of p53 function have shown that certain mutant p53 genes can cause neoplastic transformation of human bronchial epithelial cells. These results are consistent with the hypothesis that mutations in p53 can lead to loss of tumor suppressor function and gain of oncogene function.